Substituted berbines and processes for their synthesis

ABSTRACT

The present invention provides processes for the synthesis of substituted berbine compounds. Also provided are intermediates used in the synthesis of substituted berbine compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 12/552,457, filed Sep. 2, 2009, which claimspriority to U.S. Provisional Application Ser. No. 61/093,820, filed Sep.3, 2008, the disclosure of each is hereby incorporated by reference inits entirety.

FIELD OF THE INVENTION

The present invention generally relates to processes for the synthesisof substituted berbines and intermediate compounds used in thepreparation of substituted berbines.

BACKGROUND OF THE INVENTION

The berbine class of heterocyclic compounds is structurally related tothe plant alkaloid berberine. Berbine compounds have been reported tohave numerous therapeutic effects. For example, they supposedly haveantibacterial, antifungal, antiparasitic, antipyretic, antihypertensive,antidepressant, antiemetic, tranquilizing, and analgesic activities.Because of the potential therapeutic value of berbine compounds andderivatives thereof, there is a need for efficient synthesis processesfor the preparation of pure preparations of specific enantiomers.

SUMMARY OF THE INVENTION

The present invention provides processes for the synthesis ofsubstituted berbine compounds. Also provided are intermediate compoundsused in the preparation of substituted berbine compounds.

Among the various aspects of the present invention is one aspectencompassing a process for preparing compound 9 from compound 7. Theprocess comprises contacting compound 7 with an aldehyde in the presenceof a proton donor or a proton acceptor to form compound 9 according tothe following reaction scheme:

wherein:

R is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl; preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

Another aspect of the invention provides a process for preparingcompound 9 from compound 6. The process comprises contacting compound 6with an aldehyde in the presence of a asymmetric transition metalcatalyst to form compound 9 according to the following reaction scheme:

wherein:

R is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl, providedthat R² and R³ together with the aromatic carbons to which they areattached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

A further aspect of the invention encompasses a two-step method for thepreparation of compound 9 from compound 6 according to the followingreaction scheme:

wherein:

R is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

Still another aspect provides a process for the preparation of compound9x according to the following reaction scheme:

wherein:

R is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

Yet another aspect of the invention encompasses a process for preparingcompound 10. The process comprises contacting compound 8 withformaldehyde to form compound 10 according to the following reactionscheme:

wherein:

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

A further aspect of the invention provides a compound comprising Formula(I):

wherein:

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms;

R¹⁴ and R¹⁵ are independently selected from the group consisting ofhydrogen, hydroxy, and alkoxy, wherein R¹⁴ and R¹⁵ together may form ═O;

n is an integer from 1 to 3; and

— is a single or double bond.

Other aspects and features of the invention will be in part apparent andin part pointed out hereinafter.

DETAILED DESCRIPTION

The present invention provides processes for preparing substitutedberbines, as well as intermediate compounds for use in the preparationof substituted berbines. These processes of the invention are moreefficient, more specific, and provide greater yields than currentlyavailable synthesis processes. Additionally, the substituted berbinesmay be more specific, more efficacious, more potent, and/or have feweruntoward effects than unsubstituted berbines.

For ease of discussion of the substituted berbine compounds and theirintermediates, the ring atoms of a berbine compound are numbered as

diagrammed below. The substituted berbine compounds detailed herein mayhave as many as three chiral carbons, namely, C-14, C-13, and C-8.

(I) Intermediate Compounds

One aspect of the present invention encompasses compounds that may beused as intermediates in the preparation of a substituted berbinecompound. In general, the intermediate compounds comprise Formula (I):

wherein:

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms;

R¹⁴ and R¹⁵ are independently selected from the group consisting ofhydrogen, hydroxy, and alkoxy, wherein R¹⁴ and R¹⁵ together may form ═O;

n is an integer from 1 to 3; and

— is a single or double bond.

In one embodiment, the compound comprises Formula (Ia):

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are asdefined above.

In one iteration of this embodiment, R⁹, R¹⁰, R¹¹, and R¹² are eachhydrogen.

In another embodiment, the compound comprises Formula (Ib):

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are asdefined above.

In an iteration of this embodiment, R⁹, R¹⁰, R¹¹, and R¹² are eachhydrogen.

In a further embodiment, the compound comprises Formula (Ic):

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are asdefined above.

In one iteration of this embodiment, R⁹, R¹⁰, R¹¹, and R¹² are eachhydrogen. The optical activity of this compound may be either (+) or(−), and the configuration of the chiral carbons, C-14 and C-13, may beRR, RS, SR or SS, respectively.

(II) Processes for Preparing Substituted Berbine Compounds

Another aspect of the present invention provides reaction schemes forthe preparation of substituted berbine compounds. In general, theprocesses entail formation of a new ring from an asymmetric compound.

(a) Reaction Scheme 1: Conversion of Compound 7 to Compound 9

Reaction Scheme 1 provides a process in which the asymmetric compound,compound 7, undergoes a ring closure in the presence of an aldehyde anda proton donor or a proton acceptor to form the substituted berbine,compound 9, as depicted below:

wherein:

R is selected from the groups consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

In an alternative of this embodiment, R is selected from the groupconsisting of hydrogen, alkyl, aryl, carboxylic acid, and a heterocyclicring; and R⁹, R¹⁰, R¹¹, and R¹² are each hydrogen. In a preferredalternative of this embodiment, R is hydrogen.

The process of Reaction Scheme 1 comprises contacting compound 7 with analdehyde (i.e., RCHO) in the presence of a proton donor or a protonacceptor to form compound 9. Non-limiting examples of suitable aldehydesinclude formaldehyde, acetaldyhyde, propionaldehyde, butyraldehyde,cyclopropane carboxaldehyde, cyclobutane carboxaldehyde, benzaldehyde,glyoxal, glyoxylic acid, 2-furaldehyde, nicotinaldehyde, and so forth.In preferred embodiments, the aldehyde may be formaldehyde, cyclopropanecarboxaldehyde, or cyclobutane carboxaldehyde. In an exemplaryembodiment, the aldehyde may be formaldehyde. The molar ratio ofcompound 7 to aldehyde may range from about 1:0.5 to about 1:2, or morepreferably from about 1:0.8 to about 1:1.2.

In general, the proton donor or proton acceptor will have a pH of lessthan about 9. Suitable proton donors include, but are not limited to,HOAc, HCO₂H, n-PrCO₂H, PhCO₃H, MeSO₃H, poly H₃PO₄, H₃PO₄, H₂SO₄, HCl,HBr, HI, CF₃SO₃H, p-methyltoluenesulfonic acid, and combinationsthereof. Suitable proton acceptors include borate salts (such as, forexample, NaBO₃), di- and tri-basic phosphate salts (such as, forexample, Na₂HPO₄ and Na₃PO₄, and the like), bicarbonate salts (such as,for example, NaHCO₃, KHCO₃, LiHCO₃, and the like), carbonate salts (suchas, for example, Na₂CO₃, K₂CO₃, Li₂CO₃, and the like), organic bases(such as, for example, pyridine, triethylamine, diisopropylethylamine,N-methylmorpholine, N,N-dimethylaminopyridine), and mixtures thereof.Other suitable proton acceptors/proton donors includeN,N-bis-(2-hydroxyethyl)-glycine (BICINE),N-[tris(hydroxymethyl)methyl]glycine (TRICINE),tris(hydroxymethyl)aminomethane (TRIS),3-(cyclohexylamino)-1-propanesulfonic acid (CAPS),3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid (CAPSO),N-(2-hydrooxyethyl)piperazine-N′-(3-propanesulfonic acid) (EPPS),N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES),2-(N-morpholino)ethanesulfonic acid (MES),3-(N-morpholino)propanesulfonic acid (MOPS),piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES),3-{[tris(hydroxymethyl)]amino}-1-propanesulfonic acid (TAPS), andN-tris(hydroxymethyl)methyl-2-amino-ethanesulfonic acid (TES). In apreferred embodiment, the proton donor or proton acceptor may be HCO₂H,HOAc, MeSO₃H, or triethylamine. The molar ratio of compound 7 to protondonor or proton acceptor may range from 1:0.1 to about 1:5, or morepreferably from about 1:0.5 to about 1:2.

The reaction is typically conducted in the presence of a solvent. Thesolvent may be an aprotic polar solvent, a non-polar solvent, orcombinations thereof. Non-limiting examples of suitable solvents includeacetone, acetonitrile, benzene, butanone, chloroform,1,2-dichloroethane, dichloromethane, diethyl ether, diethoxymethane,dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N-dimethylpropionamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME),dimethoxymethane, dimethylacetamide (DMAC), N-methylpyrrolidinone (NMP),dioxane, ethyl acetate, ethyl formate, ethyl methyl ketone, formamide,hexamethylphosphoramide, hexane, n-propyl acetate, isopropyl acetate,methyl acetate, N-methylacetamide, N-methylformamide, methyl t-butylether, methyl butyl ketone, methylene chloride, nitrobenzene,nitromethane, propionitrile, sulfolane, tetramethylurea, tetrahydrofuran(THF), toluene, trichloromethane, and combinations thereof. In preferredembodiments, the solvent may be acetone, acetonitrile, butanone,chloroform, 1,2,-dichloroethane, dichloromethane, ethyl acetate,n-propyl acetate, isopropyl acetate, methyl t-butyl ether, methyl butylketone, tetrahydrofuran, toluene, or combinations thereof. The weightratio of solvent to compound 7 may range from about 0.5:1 to about 10:1(g/g).

The temperature of the reaction may range from about 00° C. to about120° C., and more preferably from about 10° C. to about 80° C. Thereaction is preferably performed under ambient pressure. Typically, thereaction is allowed to proceed for a sufficient period of time until thereaction is complete, as determined by chromatography (e.g., HPLC). Inthis context, a “completed reaction” generally means that the reactionmixture contains a significantly diminished amount of compound 7 and asignificantly increased amount of compound 9 compared to the amounts ofeach at the beginning of the reaction. The yield of compound 9 may be atleast about 80%, at least about 85%, at least about 90%, at least about95%, or at least about 99.9%.

The optical activity of compound 7 and compound 9 may be either (−) or(+). The configuration of C-14 in compound 7 may be either R or S, andthe configuration of C-14 and C-8, respectively, in compound 9 may beRR, RS, SR, or SS.

(b) Reaction Scheme 2: Conversion of Compound 6 to Compound 9

Reaction Scheme 2 comprises a process in which asymmetric compound 6undergoes a ring closure in the presence of an aldehyde and anasymmetric transition metal complex to form the substituted berbine,compound 9, as depicted below:

wherein:

R is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

In an alternative of this embodiment, R is selected from the groupconsisting of hydrogen, alkyl, aryl, carboxylic acid, and a heterocyclicring; and R⁹, R¹⁰, R¹¹, and R¹² are each hydrogen. In a preferredalternative of this embodiment, R is hydrogen.

The process of Reaction Scheme 2 comprises contacting compound 6 with analdehyde in the presence of an asymmetric transition metal complex toform compound 9. Examples of suitable and preferred aldehydes arepresented above in section (II)(a). The molar ratio of compound 6 toaldehyde may range from about 1:0.5 to about 1:2, or more preferablyfrom about 1:0.8 to about 1:1.2.

The asymmetric transition metal complex comprises a metal or a metal ionselected from the group consisting of Co, Cr, Ir, Ni, Pd, Pt, Rh, andRu. Exemplary asymmetric transition metal complexes includedichloro-(p-cymene)-Ru(II) dimer. The molar ratio of compound 6 toasymmetric transition metal complex may range from about 1:0.001 toabout 1:1, or more preferably from about 1:0.005 to about 1:0.5.

The reaction is typically conducted in the presence of a solvent.Examples of suitable and preferred solvents are presented above insection (II)(a). The weight ratio of solvent to compound 6 may rangefrom about 0.5:1 to about 10:1 (g/g).

The temperature of the reaction may range from about 00° C. to about120° C., and more preferably from about 10° C. to about 80° C. Thereaction is preferably performed under ambient pressure, and preferablyin an inert atmosphere (e.g., nitrogen or argon). Typically, thereaction is allowed to proceed for a sufficient period of time until thereaction is complete, as determined by chromatography (e.g., HPLC).

The yield of compound 9 generally is at least about 80%. In someembodiments, the yield of compound 9 may be about 85%, about 90%, about95%, or about 99.9%. The optical activity of compound 9 may be either(−) or (+). The configuration of C-14 and C-8, respectively, in compound9 may be RR, RS, SR, or SS.

(c) Reaction Scheme 3: Two-Step Process for the Conversion of Compound 6to Compound 9

Reaction Scheme encompasses a two-step process for the conversion ofasymmetric compound 6 to the substituted berbine, compound 9, accordingto the following scheme:

wherein

R is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

In an alternative of this embodiment, R is selected from the groupconsisting of hydrogen, alkyl, aryl, carboxylic acid, and a heterocyclicring; and R⁹, R¹⁰, R¹¹, and R¹² are each hydrogen. In a preferredalternative of this embodiment, R is hydrogen.

In step A of Reaction Scheme 3, compound 6 is contacted with anasymmetric transition metal complex to form compound 7. Examples ofsuitable and preferred asymmetric transition metal complexes arepresented above in section (II)(b). The molar ratio of compound 6 toasymmetric transition metal complex may range from about 1:0.001 toabout 1:1, or more preferably from about 1:0.005 to about 1:0.5.

In step B of Reaction Scheme 3, the asymmetric compound 7 undergoes aring closure to form compound 9. For this, compound 7 is contacted withan aldehyde in the presence of a proton donor or a proton acceptor.Examples of suitable and preferred aldehydes are presented above insection (II)(a). Likewise, examples of suitable and preferred protondonors and proton acceptors are presented in section (II)(a). The molarratio of compound 7 to aldehyde to proton donor/acceptor may range fromabout 1:0.5:0.1 to about 1:2:5, or more preferably from about 1:0.8:0.5to about 1:1.2:2.

Both steps of the process are typically performed in the presence of asolvent. Examples of suitable and preferred solvents are detailed abovein section (II)(a). The temperature of both steps of the reaction mayrange from about 0° C. to about 120° C., and more preferably from about10° C. to about 80° C. The reaction is preferably performed underambient pressure, and may be performed in an inert atmosphere (e.g.,nitrogen or argon). Typically, the reaction is allowed to proceed for asufficient period of time until the reaction is complete, as determinedby chromatography (e.g., HPLC).

The yield of compound 9 generally is at least about 80%. In someembodiments, the yield of compound 9 may be about 85%, about 90%, about95%, or about 99.9%. The optical activity of compound 7 and compound 9may be either (−) or (+). The configuration of C-14 in compound 7 may beR or S, and the configuration of C-14 and C-8, respectively, in compound9 may be RR, RS, SR, or SS.

(d) Reaction Scheme 4: Conversion of Compound 6c to Compound 9x.

Reaction Scheme 4 provides a three-step process for the conversion ofasymmetric compound 6c to the substituted berbine, compound 9x, asdepicted below:

wherein:

R is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R¹, R⁴, R⁵, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl,provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

In an alternative of this embodiment, R is selected from the groupconsisting of hydrogen, alkyl, aryl, carboxylic acid, and a heterocyclicring; and R⁹, R¹⁰, R¹¹, and R¹² are each hydrogen. In a preferredalternative of this embodiment, R is hydrogen.

(i) Step A: Conversion of Compound 6c to Compound 6x

In step A of Reaction Scheme 4, compound 6c is oxidized on C-13 to formcompound 6x. The process comprises contacting compound 6c with anoxidizing agent. Examples of oxidizing agents that may be used include,but are not limited to, dichromates (e.g., ammonium dichromate,potassium dichromate, sodium dichromate, and the like); bromates (e.g.,barium bromate, magnesium bromate, potassium bromate, sodium bromate,and the like); chlorates (e.g., ammonium chlorate, barium chlorate,calcium chlorate, potassium chlorate, sodium chlorate, and the like);chlorites (e.g., copper chlorite, lead chlorite, potassium chlorite,sodium chlorite, and the like); chloroisocyanuric acids (e.g.,trichloroisocyanuric acid, and the like); chromates (e.g., potassiumchromate, and the like); chromium oxides (e.g., chromic anhydride(chromium trioxide)); dichromates (e.g., sodium dichromate, potassiumdichromate, and the like); hydrogen peroxide; hypobromites (e.g., sodiumhypobromite, and the like); hypochlorites (e.g., calcium hypochlorite,potassium hypochlorite, sodium hypochlorite, and the like); hypoiodites(e.g., sodium hypoiodite, potassium hypoiodite, and the like); inorganicperoxides (e.g., barium peroxide, calcium peroxide, cesium peroxide,lithium peroxide, magnesium peroxide, potassium peroxide, rubidiumperoxide, sodium peroxide, strontium peroxide, and the like); iodates(e.g., calcium iodate, potassium iodate, sodium iodate, zinc iodate, andthe like); iodine oxides (e.g., diiodine pentaoxide, and the like); leadoxides (e.g., lead dioxde, and the like); manganese dioxide; nitrates(e.g., ammonium nitrate, ammonium cerium nitrate, barium nitrate,potassium nitrate, silver nitrate, sodium nitrate, and the like); nitricacid; nitrites (e.g., potassium nitrite, sodium nitrite, and the like);perchlorates (e.g., ammonium perchlorate, potassium perchlorate, sodiumperchlorate, and the like); periodates (e.g., potassium periodate,sodium periodate, and the like); periodic acids (e.g., metaperiodicacid, and the like); permanganates (e.g., ammonium permanganate,magnesium permanganate, potassium permanganate, sodium permanganate, andthe like); peroxoborates (e.g., ammonium peroxoborate, and the like);perchloric acid; peroxodisulfates (e.g., ammonium peroxodisulfates,potassium peroxydisulfate, and the like); peroxyacids (e.g.,peroxyacetic acid, peroxybenzoic acid, peroxyformic acid,trifluoroperacetic acid, and the like); organic peroxides (e.g., benzoylperoxide, and the like); tetroxides (e.g., osmium tetroxide, rutheniumtetroxide, and the like); and oxygen. As the oxygen source, air may alsobe used. The molar ratio of compound 6c to oxidizing agent may rangefrom about 1:0.5 to about 1:5, or more preferably from about 1:0.8 toabout 1:2.

Step A of the process is typically conducted in the presence of asolvent. Examples of suitable and preferred solvents are presented abovein section (II)(a). The weight ratio of solvent to compound 6c may rangefrom about 0.5:1 to about 10:1 (g/g). Step A of Reaction Scheme 4 isgenerally conducted at ambient pressure and at a temperature that rangesfrom about 00° C. to about 120° C., and more preferably from about 10°C. to about 80° C.

(ii) Step B: Conversion of Compound 6x to Compound 7x

In step B of Reaction Scheme 4, compound 6x undergoes catalyticreduction to form compound 7x. In this step of the process, compound 6xis contacted with a reducing agent such that the oxygen function on C-13is reduced to a hydroxyl group. Representative reducing agents for usein catalytic reduction methods with hydrogen include commonly usedcatalysts such as, for example, platinum catalysts (e.g., platinumblack, colloidal platinum, platinum oxide, platinum plate, platinumsponge, platinum wire, and the like), palladium catalysts (e.g.,palladium black, palladium on barium carbonate, palladium on bariumsulfate, colloidal palladium, palladium on carbon, palladium hydroxideon carbon, palladium oxide, palladium sponge, and the like), nickelcatalysts (e.g., nickel oxide, Raney nickel, reduced nickel, and thelike), cobalt catalysts (e.g., Raney cobalt, reduced cobalt, and thelike), iron catalysts (e.g., Raney iron, reduced iron, Ullmann iron, andthe like), and others. In a preferred embodiment, the reducing agent maybe sodium cyanoborohydride. The molar ratio of compound 6x to reducingagent may range from about 1:0.5 to about 1:3, or more preferably fromabout 1:0.8 to about 1:2.

Step B is generally conducted in the presence of a solvent. Examples ofsuitable and preferred solvents are presented above in section (II)(a).The weight ratio of solvent to compound 6c may range from about 0.5:1 toabout 10:1 (g/g). The reaction may be conducted at a temperature thatranges from about 00° C. to about 120° C., or more preferably from about10° C. to about 80° C. Step B generally is conducted at ambientpressure, and preferably in an inert atmosphere.

(iii) Step C: Conversion of Compound 7x to Compound 9x

In step C of Reaction Scheme 4, compound 7x undergoes a ring closure toform compound 9x. For this, compound 7x is contacted with an aldehyde inthe presence of a proton donor or a proton acceptor. Examples ofsuitable and preferred aldehydes and are presented in section (II)(a).Similarly, examples of suitable and preferred proton donors, and protonacceptors are also presented in section (II)(a). The molar ratio ofcompound 7x to aldehyde to proton donor/acceptor may range from about1:0.5:0.1 to about 1:2:5, or more preferably from about 1:0.8:0.5 toabout 1:1.2:2. Suitable solvents and weight ratios of solvent tocompound 7x are as detailed in section (II)(a). The temperature of stepC may range from about 00° C. to about 120° C., or more preferably fromabout 10° C. to about 80° C.; and reaction is generally conducted atambient pressure.

The yield of compound 9x generally is at least about 80%. In someembodiments, the yield of compound 9x may be about 85%, about 90%, about95%, or about 99.9%.

The optical activity of compound 7x, and compound 9x may be either (−)or (+). The configuration of C-13 and C-14, respectively, in compound 7xmay be RR, RS, SR, or SS, and the configuration of C-13, C-14, and C-8,respectively, in compound 9x may be RRR, RRS, RSR, RSS, SRR, SRS, SSR,or SSS.

(e) Reaction Scheme 5: Conversion of Compound 8 to Compound 10.

Reaction Scheme 5 encompasses a process for the conversion of compound 8to compound 10, as depicted below:

wherein:

R¹, R⁴, R⁵, and R⁸ are independently selected from the groups consistingof hydrogen, halogen, OR¹³, NO₂, hydrocarbyl, and substitutedhydrocarbyl;

R², R³, R⁶, and R⁷ are independently selected from the groups consistingof hydrogen, halogen, OR¹³, hydrocarbyl, and substituted hydrocarbyl;provided that R² and R³ together with the aromatic carbons to which theyare attached may form a ring comprising {—}O(CH₂)_(n)O{—}, and R⁶ and R⁷together with the aromatic carbons to which they are attached may form aring comprising {—}O(CH₂)_(n)O{—};

R⁹, R¹⁰, R¹¹, and R¹² are independently selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R¹³ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl, preferably an alkyl group with 1 to 8 carbonatoms; and

n is an integer from 1 to 3.

In an alternative of this embodiment, R⁹, R¹⁰, R¹¹, and R¹² are eachhydrogen.

The process of Reaction Scheme 5 comprises contacting compound 8 withformaldehyde to form compound 10. The molar ratio of compound 8 toformaldehyde may range from about 1:0.8 to about 1:1.2, or morepreferably from about 1:0.9 to about 1:1.1. Typically, the process isconducted in the presence of a solvent. Examples of suitable andpreferred solvents are presented above in section (II)(a). The weightratio of solvent to compound 8 may range from about 0.5:1 to about 10:1(g/g). Generally, the process is conducted at ambient pressure and at atemperature that ranges from about 00° C. to about 120° C., or morepreferably from about 10° C. to about 80° C. The yield of compound 10typically may range form about 80% to about 99.9%.

The optical activity of compound 8 and compound 10 may be (−) or (+).The configuration of C-14 in compound 8 may be R or S, and theconfiguration of C-14 in compound 10 may be R or S.

DEFINITIONS

To facilitate understanding of the invention, several terms are definedbelow.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxy group from the groupCOOH of an organic carboxylic acid, e.g., RC(O), wherein R is R¹, R¹O—,R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstituted hydrocarbyl, orheterocyclo, and R² is hydrogen, hydrocarbyl or substituted hydrocarbyl.

The term “alkyl” as used herein describes groups which are preferablylower alkyl containing from one to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl andthe like.

The term “alkenyl” as used herein describes groups which are preferablylower alkenyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include ethenyl, propenyl, isopropenyl, butenyl,isobutenyl, hexenyl, and the like.

The term “alkynyl” as used herein describes groups which are preferablylower alkynyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainand include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and thelike.

The term “aromatic” as used herein alone or as part of another groupdenotes optionally substituted homo- or heterocyclic aromatic groups.These aromatic groups are preferably monocyclic, bicyclic, or tricyclicgroups containing from 6 to 14 atoms in the ring portion. The term“aromatic” encompasses the “aryl” and “heteroaryl” groups defined below.

The term “aryl” as used herein alone or as part of another group denoteoptionally substituted homocyclic aromatic groups, preferably monocyclicor bicyclic groups containing from 6 to 12 carbons in the ring portion,such as phenyl, biphenyl, naphthyl, substituted phenyl, substitutedbiphenyl or substituted naphthyl. Phenyl and substituted phenyl are themore preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or non-aromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to theremainder of the molecule through a carbon or heteroatom. Exemplaryheterocyclo groups include heteroaromatics as described below. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy,alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano,ketals, acetals, esters and ethers.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with ahetero atom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, aryloxy, hydroxy, protected hydroxy,acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals, acetals,esters and ethers.

When introducing elements of the present invention or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

The compounds described herein may have asymmetric centers. Compoundscontaining an asymmetrically substituted atom may be isolated inoptically active or racemic form. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms. All chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated.

As various changes could be made in the above compounds and processeswithout departing from the scope of the invention, it is intended thatall matter contained in the above description and in the examples givenbelow, shall be interpreted as illustrative and not in a limiting sense.

EXAMPLES

The following examples illustrate various embodiments of the invention.

Example 1 Synthesis of Compound 8 from Compound 7

Compound 8 was prepared from compound 7 according to the followingreaction scheme:

To a reactor, isopropyl alcohol (2.0 mL/g of compound 7),tetrahydrofuran (4.0 mL/g of compound 7) and compound 7 (pre-dried untilthe limit of detection was <0.2%) were added. The suspension was cooledto −55° with stirring over a dry-ice bath. To the reactor, liquidammonia (10 mL/g of compound 7) was condensed at −55° C. The reactionmixture was cooled at −55° C. and was flushed with nitrogen for 15 min.NaOBu-t (0.35 g/g of compound 7) was added and stirred for another 15min. Lithium (cut, 0.070 g/g of compound 7) was added in three portionsto the mixture (each portion=1/3×0.070 g/g of compound 7) and thetemperature of the reaction mixture was maintained at about −45° C. to−55° C. using a dry-ice bath and by controlling the addition rate. Thereaction mixture was stirred for 50 min or until all of the lithium wasadded. If the blue color of the reaction mixture lasted for more than 30min the reaction was complete; otherwise, more lithium was added untilthe blue color persisted. Methanol (1.0 g/g of compound 7) was addedafter the reaction was deemed complete. The reaction mixture was warmedto about −28° C. to +20° C. to evaporate off most of the ammonia andstirred for another hour after the temperature reached +20° C. Degassedwater (10 mL/g of compound 7) (prepared by bubbling with nitrogen for 20min) was added under nitrogen to the above mixture. The suspension wasstirred for 30 min to form a solution (pH=12.4). A solution of aceticacid/water (HOAc 0.95 ml/g of compound 7, and H₂O 1.90 mL/g of compound7) was added to form a suspension (pH=7.8). The pH of the suspension wasadjusted to about pH 8.8-9.2 with 28% ammonium hydroxide (about 0.25mL/g of compound 7). The suspension was stirred for 1 h and filtered.The reactor was repeatedly rinsed with water (3.0 mL/g of compound 7),which was then used to wash the solid filtrate. The solid was thenwashed with water (3.0 mL/g of compound 7). The solid was dried underflowing air for 4 h and then dried in vacuum (20 inches) at 60° C. for20 h to the produce (compound 8) as an off-white solid with a yieldaround 90%.

Example 2 Synthesis of Compound 9 from Compound 7

Compound 9 was prepared from compound 7 according to the following:

Compound 7 (3 g) was refluxed in acetronitrile/chloroform (15 mL/30 mL).A solution of formaldehyde (1 M) in H₂O/acetonitrile (1:9, 11 mL) wasadded. The mixture was heated to reflux for another 3 h to form asuspension. About 20 mL of the solvent was removed by distillation. Theresulting suspension was cooled to room temperature and filtered. Thesolid was washed with isopropyl alcohol (2×5 mL) and dried under vacuumat 50° F. for 4 h to give 2.3 g of compound 9 as a solid.

Example 3 Synthesis of Compound 9 from Compound 6

Compound 9 was prepared from compound 6 according to the followingscheme:

To a reactor equipped with mechanical stirrer, triethylamine (NEt₃)(1.06 g per gram of compound 6) and acetonitrile (6 mL per gram ofcompound 6) were added. Formic acid (HCO₂H) (1.2 g per gram of compound6) was added in four portions. The exothermic reaction was maintained ata temperature of less than 80° C. during the addition. Upon cooling toroom temperature, a solution of 5HCO₂H/2NEt₃ in acetonitrile was formed.Compound 6 was added to the solution to form a suspension. Afterflushing with nitrogen for 15 min, dichloro (p-cymene)-Ru(II) dimer(0.01 g per gram of compound 6) was added. The suspension was againflushed with nitrogen for 15 min and stirred at room temperature for 10h. A solution of formaldehyde (1 M) in H₂O/acetonitrile (1:9, 3.5 mL pergram of compound 6) was added. The reaction mixture was heated over 100°C. for 2 h to form compound 9. The product was isolated as a solid bypouring the solution into an ice-cold ammonium hydroxide (NH₄OH)solution (20 mL per gram of compound 6).

Example 4 Synthesis of C-8 Cyclopropyl Derivative of Compound 9

The cyclopropyl derivative of compound 9 was prepared from the (R)isomer of compound 7 according to the following reaction scheme:

A stirred solution of compound 7 (0.5 g), methanol (3 mL), cyclopropanecarboxaldehyde (0.175 mL), triethylamine (1.86 mL), and formic acid(0.77 mL) was heated to reflux and maintained at reflux for 1 hour. Thereaction mixture was then cooled to 40° C., and dichloro(p-cymene)-Ru(II) dimer (0.01 g) was added. The resulting mixture wasstirred at 40° C. overnight. After cooling to room temperature, thereaction was diluted with water (3 mL) and the pH was adjusted to 9.0with NH₄OH. The precipitate was collected by vacuum filtration and driedto give the product as a light yellow solid. The structure of theproduct was confirmed by LC-NMR and LC-MS.

Example 5 Synthesis of C-8 Cyclobutyl Derivative of Compound 9

The cyclobutyl derivative of compound 9 was prepared from the (R) isomerof compound 7 according to the following reaction scheme:

A stirred solution of compound 7 (0.5 g), methanol (3 mL), cyclobutanecarboxaldehyde (0.175 mL), triethylamine (1.86 mL), and formic acid(0.77 mL) was heated at reflux for 1 hour. The reaction mixture was thencooled to 40° C., and dichloro (p-cymene)-Ru(II) dimer (0.01 g) wasadded. The resulting mixture was stirred at 40° C. overnight. Aftercooling to room temperature, the reaction was diluted with water (3 mL)and the pH adjusted to 9.0 with NH₄OH. The precipitate was collected byvacuum filtration and dried to give the product as a light yellow solid.The structure of the product was confirmed by LC-NMR and LC-MS.

Example 6 Alternate Synthesis of C-8 Cyclobutyl Derivative of Compound 9

The cyclobutyl derivative of compound 9 was prepared from the (R) isomerof compound 7 according to the following reaction:

A solution of compound 7 (0.5 g) and cyclobutane carboxaldehyde (0.212mL) in acetonitrile (3 mL) was heated at 40° C. for 1 hour. Sodiumcyanoborohydride (0.16 g) was then added, and the resulting mixture wasstirred at 40° C. overnight. After cooling to room temperature, thereaction mixture was diluted with water (3 mL) and the pH adjusted to9.0 with NH₄OH. The precipitate was collected by vacuum filtration anddried to give the product as a light yellow solid. The structure of theproduct was confirmed by LC-NMR and LC-MS.

What is claimed is:
 1. A process for preparing compound 9, the processcomprising forming a reaction mixture in which compound 6 is contactedwith dichloro-(p-cymene)-Ru(II) dimer and formic acid-triethylamine toform compound 7, and adding RCHO to the reaction mixture to formcompound 9 according to the following reaction scheme:

wherein: R is selected from the group consisting of hydrocarbyl andsubstituted hydrocarbyl; R¹, R², R³, and R⁴ are independently selectedfrom the group consisting of hydrogen, halogen, OR¹³, hydrocarbyl,substituted hydrocarbyl, and together R² and R³ form {—}O(CH₂)_(n)O{—};R⁵, R⁶, R⁷, and R⁸ are independently selected from the group consistingof hydrogen, halogen, OR¹³, hydrocarbyl, substituted hydrocarbyl, andtogether R⁶ and R⁷ form {—}O(CH₂)_(n)O{—}; R⁹, R¹⁰, R¹¹, and R¹² areindependently selected from the group consisting of hydrogen,hydrocarbyl, and substituted hydrocarbyl; R¹³ is selected from the groupconsisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl; and nis an integer from 1 to
 3. 2. The process of claim 1, wherein R isselected from the group consisting of alkyl, substituted alkyl, aryl,and substituted aryl, and R¹³ is alkyl.
 3. The process of claim 1,wherein each of R⁹, R¹⁰, R¹¹, and R¹² is hydrogen.
 4. The process ofclaim 1, wherein R¹, R², R³, and R⁴ are independently selected from thegroup consisting of hydrogen, OR¹³, and together R² and R³ form{—}O(CH₂)_(n)O{—}; and R⁵, R⁶, R⁷, and R⁸ are independently selectedfrom the group consisting of hydrogen, OR¹³, and together R⁶ and R⁷ form{—}O(CH₂)_(n)O{—}; wherein R¹³ is hydrogen or an alkyl having 1 to 8carbon atoms, and n is 1 to
 3. 5. The process of claim 1, whereincompound 7 and RCHO are present at a molar ratio of about 1:0.5 to about1:2.
 6. The process of claim 1, wherein the reaction is conducted in thepresence of a solvent selected from the group consisting of acetone,acetonitrile, butanone, chloroform, 1,2,-dichloroethane,dichloromethane, ethyl acetate, n-propyl acetate, isopropyl acetate,methanol, methyl t-butyl ether, methyl butyl ketone, tetrahydrofuran,toluene, and combinations thereof.
 7. The process of claim 1, whereinthe reaction is conducted is conducted at a temperature ranging fromabout 00° C. to about 120° C.
 8. The process of claim 1, whereincompound 9 has a yield of at least about 80%.
 9. The process of claim 1,wherein R is alkyl; R¹, R², R³, and R⁴ are independently selected fromthe group consisting of hydrogen, OR¹³, and together R² and R³ form{—}O(CH₂)O{—}; R⁵, R⁶, R⁷, and R⁸ are independently selected from thegroup consisting of hydrogen, OR¹³, and together R⁶ and R⁷ form{—}O(CH₂)O{—}; and each of R⁹, R¹⁰, R¹¹, and R¹² is hydrogen, whereinR¹³ is hydrogen or methyl.
 10. The process of claim 9, wherein thereaction is conducted in the presence of a solvent selected from thegroup consisting of acetonitrile, chloroform, methanol, and combinationsthereof.
 11. The process of claim 10 wherein the reaction is conductedis conducted at a temperature ranging from about 10° C. to about 80° C.12. The process of claim 11, wherein compound 9 has a yield of about 80%to about 99.9%.